A Study in a Genetically Homogenous Population Exposed to Different Environment

Batsheva Kerem, Ph.D.

Funded in September, 2003: $300000 for 3 years

Identifying Genetic Factors Conferring Predisposition to Asthma

This proposed project will elucidate the genetic factors that predispose people to develop asthma and the biochemical pathways associated with the disease. This could lead to a better understanding of eventual means that could be used to prevent the disease, and improved therapeutic approaches.

Asthma is an inherited, complex immune system disorder that is influenced by environmental factors. It forms part of the spectrum of atopic diseases characterized by airway inflammation and related intermittent respiratory symptoms and reversible airflow obstruction. Disease expression is influenced by interactions between multiple major and minor genes and is modulated by interacting environmental factors. The relative contribution of each factor to the pathogenesis of the disease has not been established. The investigators propose studying genes associated with the disease in the relatively isolated and highly inbred Cochin population that has a high prevalence of asthma. The Cochin population migrated to Israel from the capital of Kerala in Southwest India. The community was isolated in India, and they migrated to two specific locations in Israel, one in the Negev desert, the other in the Jerusalem mountains. Initial studies suggest differences exist between those with asthma in the mountains compared to those living in the desert.

The researchers first will use genetic linkage studies to identify the candidate genes. They will construct pedigrees of affected individuals, use genome mapping to identify candidate gene regions and then identify small areas of genes, called "SNP's." This may lead to the identification of candidate proteins produced by the genes to carry out their functions. Further study of the molecular basis of the disease will involve using DNA microarrays to identify genes and biochemical pathways associated with the disease. Environmental factors are specific and well defined, and will be considered separately from these genetic factors. By studying an inbred population with a high prevalence of asthma, the investigators expect to be able to determine the relative importance of a small number of factors in the disease.

Interaction Between Environmental and Genetic Factors in Asthma and Atpoy: A Study in a Genetically Homogenous Population Exposed to Different Environment

Asthma and allergy are common chronic diseases with prevalence estimated at 10-25% of the population. They show a strong genetic component that follows a complex mode of inheritance, involving interactions between exogenous environmental factors (allergens, infections, noxious environmental stimuli) and genetic factors.

We propose to study the complex interaction between environmental factors and the genetics of asthma and atopy in one of the most isolated Jewish groups, the Jews of Cochin. This is a genetically homogenous population, isolated in India for more than 1000 years, that immigrated to Israel about 50 years ago and settled in villages at two different geographic and environmental areas. We have defined the clinical phenotype of 800 individuals with asthma and allergy living in the desert and in the Jerusalem Mountain areas. The results indicated a high prevalence of allergy and asthma among the Cochin Jews (23.7% had asthma, and 29.5% had allergy) relative to controls. However, significantly lower incidence of asthma and allergy was found among those living in the desert (19% and 23%) compared to the community living near Jerusalem (28% and 35%).

The aim of this project is to identify genes which are up- or down-regulated in asthma and/or allergy, in the Chochin Jews populations, using micro arrays representing 30,000 human genes. Identification of differences in expression pattern between patients living in the desert and Jerusalem might shade a new light on the effect of the environment on the development of asthma and allergy.

Batsheva Kerem, Ph.D.

Professor Batsheva Kerem, Ph.D., received a B.Sc from the Hebrew University in 1979, received a Ph.D. there in 1986, and then completed a three-year post doctorate fellowship in the Department of Genetics, the Research Institute of the Hospital for Sick Children, Toronto, Canada. During her post doctorate fellowship, Prof. Kerem was part of the group that identified the cystic fibrosis gene. After returning to Israel in 1990, she established a research group. She currently is a Full Professor in the Department of Genetics, the Life Sciences Institute of the Hebrew University.

Her research group studies the molecular bases of diseases. Prof. Kerem's main interest is in understanding the molecular basis of disease variability among patients carrying the same genetic differences. This includes genetic modifiers and environmental factors. Her recent studies are focused on cystic fibrosis, asthma, allergy, and cancer. In cystic fibrosis, she studies modifier genes that modulate disease severity among patients carrying "splicing" or "stop" mutations. In cancer, she studies the role of specific regions defined as fragile sites in underlying chromosomal instability in cancer cells.

Professor Eitan Kerem, M.D., graduated from the Hebrew University Hadassah Medical School in 1982, completed a pediatric residency, took a three-year fellowship in Pediatric Pulmonology at the Chest Division, the Hospital for Sick Children, Toronto, Canada, and returned to Israel in 1990. He is currently Associate Professor in Pediatrics at the Hebrew University, Hadassah Medical School, and Head of the Department of Pediatrics at Hadassah University Hospital, Jerusalem.

His research concerns the association between genotype and phenotype in respiratory diseases and the interaction of environmental factors with genetic diseases and their influence on disease severity. His recent studies focused on the genetic markers of asthma and allergy in closed populations, and disease variability in closed populations exposed to different environments. His studies on cystic fibrosis examine prognostic factors for disease severity and prediction of mortality, molecular mechanisms involved in disease variability, and development of new mutation-specific pharmacological therapies to correct the basic defects in cystic fibrosis.

Lay Results:
Asthma and allergy are common chronic diseases with prevalence estimated at 10-25% of the population. They show a strong genetic component that follows a complex mode of inheritance, involving interactions between environmental and genetic factors. Our studied population comprised Cochin Jews, an isolated population in which the incidence of athma and allergy is extermely high, reaching 40% of the individuals. We had developed, using both classical genetics and modern molecular biology, a potential tool to diagnose the disease in a blood sample. The results revealed a set of genes expressed specifically in asthma patients and therefore provide a “signature or fingerprinting” of the disease.

Scientific Results:
Asthma and allergy are common chronic diseases with prevalence estimated at 10-25% of the population. They show a strong genetic component that follows a complex mode of inheritance, involving interactions between environmental and genetic factors. Our studied population comprised Cochin Jews, an isolated population in which the incidence of athma and allergy is extermely high, reaching 40% of the individuals. We used two complementary approaches: 1. linkage analysis on the entire genome using 400 microsatellite polymorphic markers and 2. microarray hybridization and analysis of RNA from 98 individuals to arrays comprising the whole trqnscriptome (44,000 transcripts). Together, we have identified 199 genes able to differentiate between asthmatic and non-asthmatic patients using a blood sample. This gene signature or fingerprint has the potential to become a diagnostic tool for asthma.